Pharma Strategy Blog

This morning my emails greeted me with an announcement that the long awaited phase III SUCCEED trial data in soft tissue sarcomas from Ariad and Merck has been announced:

“… showing that ridaforolimus, an investigational oral mTOR inhibitor, met the primary endpoint of improved progression-free survival (PFS) compared to placebo in the Phase 3 SUCCEED trial conducted in patients with metastatic soft-tissue or bone sarcomas who previously had a favorable response to chemotherapy.

Merck is currently developing ridaforolimus in multiple cancer indications under an exclusive license and collaboration agreement with ARIAD.   Complete findings from the SUCCEED trial will be submitted for presentation at an upcoming medical meeting this year.”

In the analyst teleconference I just listened to, the CEO Harvey Berger also stated that aside from presenting the data at a meeting this year, Merck was planning on filing the data with the regulatory authorities.

The good news is that no new safety signals have emerged and the common side effects reported previously, ie stomatitis (mouth sores), fatigue, diarrhea and thrombocytopenia appear unchanged.

Correspondence and interviews with a number of the SUCCEED trialists in the US and EU over the last year has taught me that ridaforolimus is generally well tolerated and quite a few patients have experienced prolonged stable disease (SD) while on ridaforolimus maintenance therapy between chemotherapy.

According to Ariad, the initial aggregated data from SUCCEED was as follows:

“Based on the full analysis of 552 PFS events in 711 patients, determined by an independent review committee, the blinded prospective study achieved its primary endpoint, with a statistically significant (p=0.0001) 28 percent reduction by ridaforolimus in the risk of progression compared to placebo (hazard ratio=0.72). Determination of median PFS for each arm of the trial demonstrated that ridaforolimus treatment resulted in a statistically significant 21 percent (3.1 week) improvement in median PFS (ridaforolimus, 17.7 weeks vs. placebo, 14.6 weeks).

Based on the full analysis of PFS determined by the investigative sites, there also was a statistically significant (p<0.0001) 31 percent reduction by ridaforolimus in the risk of progression compared to placebo (hazard ratio=0.69).  Ridaforolimus treatment resulted in a statistically significant 52 percent (7.7 week) improvement in median PFS (ridaforolimus, 22.4 weeks vs. placebo, 14.7 weeks).”

There are several important things to note here:

1. The PFS is less than a month, but highly significant
2. The conditions for the SPA (primary endpoint was PFS) appear to have been met
3. The last patient enrolled early last year, so hopefully the OS data (secondary endpoint) will be ready by the filing and will be positive
4. The excellent hazard ratios suggest that the curves are well separated, leading me to think/hope that the OS might actually be more encouraging than PFS
5. PFS is a difficult surrogate end point to measure; many trials end up with a difference between investigator estimate and central review as a result

We also need to look at these results in the context of soft tissue sarcomas (STS) as a disease.  By this, I’m thinking about the following issues:

• STS is a heterogeneous disease made up of many different subtypes
• It is a difficult to treat, aggressive disease and many patients are treated with multiple lines of chemotherapy to progression but sadly still relapse as resistance develops
• Some subtypes are highly chemosensitive, some are not
• Stable disease and quality of life are valuable to people with sarcoma
• The danger of a ‘catch-all’ trial is that the non-responders cancel out the responders, lowering the overall response rate
• Did any particular subsets do better on ridaforolimus than others?
• Did any biomarkers emerge around mTOR, PI3-kinase, AKT, MEK or some other factor?
• What factors were associated with the development of resistance?
• If so, would this help us learn what might be a useful combination approach going forward?

Overall, based on what I’ve seen, this data looks promising so far and I’m keen to see more granular data when it is presented at a scientific meeting soon… Perhaps the data made the ASCO late breaking abstract cut-off this month?